EP0144986B1 - Dérivés d'indole-3-carboxamides - Google Patents

Dérivés d'indole-3-carboxamides Download PDF

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Publication number
EP0144986B1
EP0144986B1 EP84114878A EP84114878A EP0144986B1 EP 0144986 B1 EP0144986 B1 EP 0144986B1 EP 84114878 A EP84114878 A EP 84114878A EP 84114878 A EP84114878 A EP 84114878A EP 0144986 B1 EP0144986 B1 EP 0144986B1
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Prior art keywords
compound
group
formula
benzyl
sub
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EP84114878A
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German (de)
English (en)
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EP0144986A2 (fr
EP0144986A3 (en
Inventor
Tetsuya Tahara
Takemi Fukuda
Michihide Setoguchi
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Welfide Corp
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Welfide Corp
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Priority to AT84114878T priority Critical patent/ATE25682T1/de
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Publication of EP0144986A3 publication Critical patent/EP0144986A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S47/00—Plant husbandry
    • Y10S47/01—Methods of plant-breeding and including chromosome multiplication

Definitions

  • the present invention relates to novel and therapeutically valuable indole-3-carbcixamide derivatives, pharmaceutically acceptable acid addition salts thereof and hydrates thereof, method for preparing the indole-3-carboxamide derivatives and pharmaceutical compositions containing at least one indole-3-carboxamide derivative.
  • Benzamide compounds represented by sulpiride has been used as antischizophrenic drugs, and are well known to have less side effects on the extrapyramidal system and weak cataleptogenic activity unlike butyrophenone compounds such as haloperidol or phenothiazine compounds such as chlorpromazine. Sulpiride, however, is also reported to have a low bioavailability in oral administration and poor penetration across blood-brain barrier. Sulpiride is also used as anti-ulcer agents.
  • indoramin (INN, 3-[2-(4-benzamido-1-piperidyl)-ethyl]indole) is selected as the compound having stronger antihypertensive activity, and also exhibits anti-histaminic activity and anticonvulsant activity.
  • indoramin shows weak apomorphine-antagonistic activity, but it cannot be used as neuroleptic and anxiolytic drugs because of exhibition of relatively strong antihypertensive activity.
  • Other known 3-indoleethylamine compounds mentioned above do not show apomorphine-antagonistic activity, in practice.
  • benzamide compounds have dopamine-antagonistic activity as a main activity
  • the present inventors have synthesized a series of compounds in place of the phenyl moiety of the benzamide compounds into indole moiety which is the nucleus of serotonin, and investigated their pharmacological activities.
  • novel indole-3-carboxamide derivatives, pharmaceutically acceptable acid addition salts thereof and hydrates thereof have excellent oral uptake and blood-brain barrier permeability, and potent anti-dopamine action with higher selectivity to the mesolimbic system, and further serotonin- and noradrenaline-antagonistic activities, and are useful as neuroleptic and anxiolytic drugs, and for the prevention and treatment of psychosomatic disturbances such as gasteric ulcer and duodenal ulcer.
  • the indole-3-carboxamide derivatives of the present invention are represented by the following formula: wherein R' is a hydrogen atom, a C ' - 4 alkyl group, a phenyl group which may be optionally substituted by a halogen atom or the benzene ring or a phenyl-C 1-4 alkyl group which may be optionally substituted by a halogen atom on the benzene ring; R 2 is a hydrogen atom or a C ' - 4 alkyl group; R 3 is a hydrogen atom, a halogen atom, a C '-4 alkyl group, a hydroxyl group, a C ' - 4 alkoxy group; R 4 is a hydrogen atom, a C 1-4 alkyl group, a C 3 - 7 cycloalkyl group, an allyl group or a benzyl group which may be optionally substituted by a halogen atom on the benzene
  • a C 1-4 alkyl group means methyl, ethyl, propyl, isopropyl, butyl or tertiary butyl;
  • a halogen atom means fluorine, chlorine, bromine or iodine;
  • a C ' - 4 alkoxy group means methoxy, ethoxy, propoxy or butoxy;
  • a C 3 - 7 cycloalkyl group means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • the compounds of formula (I) can be, for example, prepared by the following processes of:
  • reaction of process (1) is carried out by a conventional amide preparation method or a peptide synthesis method.
  • the reaction is carried out in an inert solvent at room temperature or under cooling or heating in the presence of a condensing agent such as a carbodiimide (e.g., dicyclohexylcarbodiimide), titanium tetrachloride, a phosphorus halide (e.g., phosphorus trichloride or phosphorus oxychloride), diphenylphosphoryl azide or a quaternary pyridinium salt (e.g., 2-chloro-N-methylpyridinium iodide or 3-methane-sulfonyloxy-N-methylpyridinium iodide).
  • a condensing agent such as a carbodiimide (e.g., dicyclohexylcarbodiimide), titanium tetrachloride, a phosphorus halide (e.g., phosphorus trichloride or phosphorus oxychloride), diphenylphosphoryl
  • an acid halide e.g., an acid chloride or an acid bromide
  • a mixed acid anhydride e.g., a mixed acid anhydride with a carbonic acid hemi lower alkyl ester, a lower alkanoic acid or a mixed acid anhydride with a lower alkylphosphoric acid
  • the reaction is carried out in an inert solvent at room temperature, or under cooling or heating, preferably in the presence of a deacidifying agent such as an organic base (e.g., triethylamine or pyridine) or an inorganic base (e.g. sodium hydrogencarbonate, an alkali carbonate or an alkali hydroxide).
  • an organic base e.g., triethylamine or pyridine
  • an inorganic base e.g. sodium hydrogencarbonate, an alkali carbonate or an alkali hydroxide
  • reaction is carried out in an inert solvent at room temperature or under refluxing, if desired, in the presence of a strong basic catalyst like sodium alkoxide.
  • active ester e.g., p-nitrophenyl ester, p-nitrobenzyl ester or p-chlorophenyl ester
  • the compounds of formula (II) wherein R 3 is a hydroxyl group may be used by means of the protection of the hydroxyl group with a lower alkoxy group, a benzyloxy group, a lower alkanoyloxy group, a benzoyloxy group or a dihydropyranyloxy group for acylation of the compounds of formula (III) as mentioned above. And then the protecting group of the resulting compounds can be removed by treating with an acid or alkali or subjecting to catalytic hydrogenation on palladium carbon or platinum oxide and so on, if desired.
  • the compounds of formula (I) wherein R 4 is a hydrogen atom can be obtained.
  • the reaction of process (2) is preferably carried out in acetic acid, and the reaction of process (3) is carried out in an inert solvent in the presence of a catalyst such as palladium carbon, Raney nickel or platinum oxide.
  • the alkylating agent employed in process (5) includes a lower alkyl halide or an ester of a lower alkanol with p-toluenesulfonic acid, methanesulfonic acid or sulfuric acid.
  • the alkylating reaction is usually carried out after treating the compounds of formula (VIII) with sodium hydride or sodium amide in an inert solvent.
  • any inert solvent can be used in practicing the above reaction, and preferably water, a lower alkanol (e.g., methanol, ethanol, or isopropanol), an ester (e.g., ethyl acetate), an aromatic hydrocarbon (e.g., benzene or toluene), a halogenated hydrocarbon (e.g., methylene chloride or chloroform), a ketone (e.g., acetone or methyl ethyl ketone), an ether (e.g., diethyl ether, tetrahydrofuran or dioxane), dimethylformamide or dimethyl sulfoxide, or a mixture thereof are used.
  • a lower alkanol e.g., methanol, ethanol, or isopropanol
  • an ester e.g., ethyl acetate
  • an aromatic hydrocarbon e.g., benzene or to
  • the compounds of the present invention are prepared as a racemate by using the starting compounds having a chiral carbon atom.
  • the present invention also embraces individual optically active isomers.
  • the optically active compounds of formula (1) can, if desired, be prepared by resolving the resulting racemate in a conventional manner with an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, mandelic acid or 10-camphorsulfonic acid) or by using the optically active compounds previously prepared as a starting compound.
  • an optically active acid e.g., tartaric acid, dibenzoyltartaric acid, mandelic acid or 10-camphorsulfonic acid
  • the compounds of the present invention can, if desired, be converted into pharmaceutically acceptable acid addition salts thereof in a conventional manner by treating with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or sulfuric acid) or an organic acid (e.g., p-toluenesulfonic acid, methanesulfonic acid, citric acid, butyric acid, maleic acid, fumaric acid or tartaric acid).
  • an inorganic acid e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or sulfuric acid
  • organic acid e.g., p-toluenesulfonic acid, methanesulfonic acid, citric acid, butyric acid, maleic acid, fumaric acid or tartaric acid.
  • the compounds of formula (I), pharmaceutically acceptable acid addition salts thereof and hydrates thereof exhibit potent anti-dopamine activity as shown in the following pharmacological experiment, but do not show antihypertensive activity or antihistaminic activity, and are useful as neuroleptic drugs without extrapyramidal side effect and the other undesirable adverse effects such as hypotension.
  • mice Groups of 5 male dd-strain mice were used. Test compounds were orally or intraperitoneally administered and 60 minutes thereafter, 0.5 mg/kg of apomorphine hydrochloride was subcutaneously administered. Immediately thereafter, spontaneous motility of the mice was measured with the aid of Animex (manufactured by Columbus Company, U.S.A.) for 20 minutes. The procedure was repeated three times with respective groups. The dose of test compounds required for 50% suppression of spontaneous motility of control group was graphically intraporated and determined as ED 50 value. The results are shown in Table 1.
  • the acute toxicity of the compounds of the present invention was studied in 5 male mice weighing 30 to 45 g. The mice were observed for 5 days after the oral administration of the test compound, and the mortality was calculated. All animals were survived even at the dose of 500 mg/kg of compound of Example 2.
  • the compounds of the invention represented by formula (I), in base or salt form can be safely administered as neuroleptic and anxiolytic drugs, and for the prevention and treatment of psychosomatic disturbances, in the form of a pharmaceutical preparation with a suitable and conventional pharmaceutically acceptable carrier, without adversely affecting the patients.
  • the pharmaceutical preparation can take any conventional form such as tablets, capsules, granules, powders or injectable solutions.
  • the single dose of the compound of the invention for human adults usually ranges from about 0.1 mg/ kg to about 10 mg/kg, but it may vary depending upon the age, body weight, and/or severity of the conditions to be treated as well as the response to the medication.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)

Claims (9)

1. Procédé de préparation de dérivés d'indole-3-carboxamides de la formule:
Figure imgb0056
y compris de leurs sels d'addition d'acide et/ou hydrates pharmaceutiquement acceptables, dans laquelle R' représente un atome d'hydrogène, un groupe alkyle en C1―C4 ou un groupe phényle qui peut être éventuellement substitué par un atome d'halogène sur le noyau benzénique ou un groupe phényl-alkyle en C1―C4 qui peut être éventuellement substitué par un atome d'halogène sur le noyau benzénique, R2 représente un atome d'hydrogène ou un groupe alkyle en C1―C4, R3 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1―C4, un groupe hydroxy ou un groupe alcoxy en C,-C4, R4 représente un atome d'hydrogène, un groupe alkyle en C1―C4, un groupe cycloalkyle en C3―C7, un groupe allyle ou un groupe benzyle qui peut être éventuellement substitué par un atome d'halogène sur le noyau benzénique ou par un groupe méthyle sur le carbone en a, RS représente un atome d'hydrogène ou un groupe alkyle en C1―C4, m est égal à 0 ou 1 et n est un nombre entier de 1 à 3, par l'un quelconque des processus suivants:
(1) la mise en réaction d'un composé de la formule:
Figure imgb0057
dans laquelle chaque symbole est tel que défini précédemment, ou d'un dérivé fonctionnel de celui-ci avec un composé de la formule:
Figure imgb0058
dans laquelle chaque symbole est tel que défini précédemment, à la condition que R4 soit différent d'un atome d'hydrogène; ou
(2) le traitement d'un composé de la formule:
Figure imgb0059
dans laquelle
Figure imgb0060
 représente un groupe méthyle ou un group benzyle et les autres symboles sont tels que définis précédemment, par de l'acide bromhydrique; ou
(3) la soumission d'un composé de la formule:
Figure imgb0061
dans laquelle chaque symbole est tel que défini précédemment, à une hydrogénation catalytique; ou
(4) la mise en réaction d'un composé de la formule:
Figure imgb0062
dans laquelle chaque symbole est tel que défini précédemment, avec un composé de la formule:
Figure imgb0063
dans laquelle Rb est tel que défini pour R4, à l'exception d'un atome d'hydrogène est X représente un group réactif; ou bien
(5) la mise en réaction d'un composé de la formule:
Figure imgb0064
dans laquelle chaque symbole est tel que défini précédemment, avec un agent d'alkylation; et
(6) la conversion, suivant les nécessités, du composé ainsi obtenu en un sel d'addition d'acide pharmaceutiquement acceptable de celui-ci.
2. Procédé de préparation d'un composé de la revendication 1: le N-(1-benzyl-4-pipéridyl)-5-fluoro-2-méthylindole-3-carboxamide suivant la revendication 1.
3. Procédé de préparation d'un composé de la revendication 1: le N-(1-benzyl-4-pipéridyl)-5-fluoroindole-3-carboxamide suivant la revendication 1.
4. Procédé de préparation d'un composé de la revendication 1: le N-(1-benzyl--4-pipéridyl)-2-méthylindole-3-carboxamide suivant la revendication 1.
5. Procédé de préparation d'un composé de la revendication 1: le N-(1-benzyl-4-pipéridyl)indole-3-carboxamide suivant la revendication 1.
6. Procédé de préparation d'un composé de la revendication 1: le N-(1-benzyl-3-pyrrolidinyl)-5-fluoro-2-méthylindole-3-carboxamide suivant la revendication 1.
7. Procédé de préparation d'un composé de la revendication 1: le N-[1-(p-chlorobenzyl)-4-pipéridyl]-5-fluoro-2-méthylindole-3-carboxamide suivant la revendication 1.
8. Procédé de préparation d'une composition pharmaceutique comprenant la formulation d'une quantité thérapeutiquement efficace d'un composé de la revendication 1 et un support pharmaceutiquement acceptable.
EP84114878A 1983-12-08 1984-12-06 Dérivés d'indole-3-carboxamides Expired EP0144986B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT84114878T ATE25682T1 (de) 1983-12-08 1984-12-06 Indol-3-carboxamid-derivate.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP232514/83 1983-12-08
JP58232514A JPS60123485A (ja) 1983-12-08 1983-12-08 インド−ル−３−カルボキサミド誘導体

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EP0144986A2 EP0144986A2 (fr) 1985-06-19
EP0144986A3 EP0144986A3 (en) 1985-07-24
EP0144986B1 true EP0144986B1 (fr) 1987-03-04

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US (1) US4616009A (fr)
EP (1) EP0144986B1 (fr)
JP (1) JPS60123485A (fr)
KR (1) KR910006863B1 (fr)
AT (1) ATE25682T1 (fr)
CA (1) CA1279319C (fr)
DE (1) DE3462504D1 (fr)
ES (1) ES8604571A1 (fr)

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KR850004482A (ko) 1985-07-15
JPS6348272B2 (fr) 1988-09-28
JPS60123485A (ja) 1985-07-02
US4616009A (en) 1986-10-07
ES8604571A1 (es) 1986-02-01
EP0144986A2 (fr) 1985-06-19
KR910006863B1 (ko) 1991-09-09
DE3462504D1 (de) 1987-04-09
CA1279319C (fr) 1991-01-22
ATE25682T1 (de) 1987-03-15
ES538418A0 (es) 1986-02-01
EP0144986A3 (en) 1985-07-24

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